A number of 3α-hydroxy, 3β-substituted-5α-pregnan-20-ones steroid derivatives have proven effective in modulating the GABA receptor chloride ionophore complex (GR complex) in vitro and exhibit useful therapeutic effects in animal models of human CNS disorders. Foremost among them is 3α-hydroxy, 3β-methyl-5α-pregnan-20-one (Ganaxolone, GNX, 1) which has been shown to stimulate the GR complex and demonstrates a variety of beneficial physiological effects in vivo. Ganaxolone 1 is being tested in advanced clinical trials for epilepsy and may have utility in a number of other CNS disorders. The high doses of ganaxolone required for efficacious treatment in humans (>1 g/day) necessitate the need for an efficient and low cost manufacturing process (Nohria and Giller, J. Am. Soc. Exp. Neurotherapeutics, (2007) 4: 102-105).

The most direct approach to the synthesis of ganaxolone is via regioselective and stereoselective attack at the C-3 carbonyl of 5α-pregnane 3,20-dione (Dione 2) by an organometallic methylating agents such as methyl Grignard or methyllithium. Direct methylation of 5α-pregnane 3,20-dione with methyllithium or methyl Grignard to prepare ganaxolone has not been possible as irreversible attack of both the C3 and C20 carbonyl groups by carbon anions yields complex mixtures of products.

As the undesired products from methylation of dione 2 have similar physical properties to of ganaxolone, one must obtain ganaxolone from an organometallic methylation reaction of Dione 2 with less than 10% of any single impurity to avoid multiple purification steps which also lower the effective yield and increase the manufacturing costs to obtain pharmaceutically pure ganaxolone (no single impurity >0.1%).
The standard approach to the synthesis of Ganaxolone 1 involves protection of the C-20 carbonyl of 3α-hydroxy-5α-pregnane 20-one prior to oxidation to react with an organometallic methylating agent at position 3 to introduce the 3β-methyl group followed by hydrolysis of the ketal at C-20 (Hogenkamp et al., J. Med. Chem., (1997) 40: 61-72). The disadvantage of this approach is that it adds at least two additional steps to the overall synthesis, first protection of the C20 carbonyl, removal of the protecting group after introduction of the 3β-methyl group.
More importantly, the stereoselectivity is quite poor resulting in nearly equal amount of the 3α and 3β isomers. This increases the cost and complexity of the synthesis and lowers the overall yield for the process.
Another method for the synthesis of ganaxolone (1) is provided by U.S. Pat. No. 5,319,115 and the literature (He et. al., Zhongguo Xinyao Zazhi (2005), 14(8), 1025-1026) wherein dione 2 is reacted with Corey's Reagent (trimethylsulfoxonium iodide) and potassium t-butoxide in tetrahydrofuran via a reversible thermodynamically controlled reaction (Johnson et al., J. Am. Chem. Soc., (1973), 95 (22), 7424-7431) to generate the more stable epoxide isomer (1-((2′R,5S,8R,9S,10S,13S,14S,17S)-10,13-dimethylhexadecahydrospiro [cyclopenta[a]phenanthrene-3,2′-oxirane]-17-yl)ethanone) at C3. The epoxide is reduced under a variety of conditions including nucleophilic opening of the epoxide with potassium iodide and reducing the resulting iodide via hydrogenation to afford ganaxolone 1. This synthesis requires isolation and purification of the intermediate epoxide as well as many manipulations and an expensive hydrogenation step all of which contribute to a more expensive and lengthy process. The reaction of Corey's reagent with Dione 2 followed by reduction of the epoxide yields a by-product 17-hydroxyganaxolone 8 which is difficult to remove. Obtaining purified ganaxolone via the Corey reagent route has often produced levels of 17-hydroxyganaxolone >0.1% by HPLC.
There remains a need for an efficient and cost effect ganaxolone synthesis, which provides high purity ganaxolone.